According to Rome II which are diagnostic criteria of the entire functional gastrointestinal disorders, “the state in which lower gastrointestinal tract symptoms are observed, but an organic disease is not found” is diagnosed as a functional bowel disorder. The functional bowel disorders having characteristic syndromes are subclassified into irritable bowel syndrome (IBS), functional diarrhea, functional constipation and functional abdominal distension. Functional diarrhea is a group of diseases whose main symptom is chronic diarrhea without abdominal pain. Functional constipation is a group of diseases whose main symptom is chronic constipation without abdominal pain. Functional abdominal distension is a group of diseases whose main symptoms are abdominal distension and gas, in which abdominal pain is not predominant. Irritable bowel syndrome are diseases which are not classified into any of the functional diarrhea, functional constipation and functional abdominal distension, and may be thought to be a generic name of diarrheal diseases with abdominal pain (diarrheal IBS), costive diseases with abdominal pain (costive IBS) and diseases in which diarrhea and constipation both with abdominal pain alternately appear (alternating IBS).
In the diarrheal IBS, frequent diarrhea in a small amount continues for a long time. Against this symptom, to inhibit contraction of smooth muscle, an anticholinergic drug with antispasmodic property is often used, and a drug for controlling intestinal function is often used in combination. Costive IBS is a spastic constipation caused by enhanced movement of intestinal tract. Against this symptom, a method in which the hardness of feces is controlled by using a saline purgative is often employed. In alternating IBS, diarrhea and constipation alternate with time, and it is difficult to cure this disease with a drug, but basically, a gastrointestinal motility improvement agent is used for alleviating the symptom. However, up to now, a curative drug for irritable bowel syndrome does not exist, and merely symptomatic treatments for the purpose of alleviation of each type of symptoms are performed.
In the meantime, as for the therapeutic effect of the compounds having morphinan skeleton against functional bowel disorders, especially irritable bowel syndrome, a low dosage prescription of naltrexone which is an opioid receptor antagonist has been disclosed (Patent Literature 1). Although data showing pharmacological effects are not shown, it has been suggested that a group of compounds including a specific 6-amino substituted morphinan derivative may be applied to bowel diseases (Patent Literatures 2 and 3). Further, it has been reported that loperamide (Non-Patent Literature 1) which is an opioid agonist, and fedotozine which is a peripheral opioid κ agonist are effective for irritable bowel syndrome, although these compounds have no structural similarity with the compounds contained in the agent according to the present invention.
On the other hand, it has been disclosed that morphinan derivatives having a nitrogen-containing cyclic substituent at 6-position used in the present invention are useful as a therapeutic or prophylactic agent for frequent urination or urinary incontinence, as an antipruritic, or as an analgesic (Patent Literatures 4, 5 and 6. The use as an analgesic was disclosed after the priority date of the present application). It has also been reported that morphinan derivatives including those having a nitrogen-containing cyclic substituent at 6-position are useful as an analgesic, diuretic, antitussive, and as a brain cell-protecting agent (Patent Literature 7). Further, some references (Patent Literatures 8 and 9, Non-Patent Literatures 3, 4 and 5) report that morphinan derivatives having a nitrogen-containing cyclic substituent included in those used in the present invention, none of the references suggest the effect against the functional bowel disorders.
There is no relationship between the structures of the compounds disclosed in the above-described prior art references as well as their pharmacological effects through the opioid receptor and the effects of the compounds used in the present invention against the functional bowel disorders. Thus, these references do not infer at all the significant and useful therapeutic or prophylactic effect of the compounds characterized by having a nitrogen-containing cyclic substituent at the 6-position of the morphinan structure.
Patent Literature 1: International Publication WO 00/051592
Patent Literature 2: International Publication WO 03/051888
Patent Literature 3: International Publication WO 02/036573
Patent Literature 4: International Publication WO 04/033457
Patent Literature 5: International Publication WO 05/094826
Patent Literature 6: International Publication WO 06/049248
Patent Literature 7: International Publication WO 95/03308
Patent Literature 8: Japanese Patent Publication (Kokoku) No. 41-18824
Patent Literature 9: Japanese Patent Publication (Kokoku) No. 41-18826
Non-Patent Literature 1: Talley N. J., Am. J. Gastroenterol, 98(4), 750-8, 2003.
Non-Patent Literature 2: Dapoigny M. et. al., Dig. Dis. Sci., 40(10), 2244-9, 1995.
Non-Patent Literature 3: Simon C. et. al., Tetrahedron, 50, 9757, 1994.
Non-Patent Literature 4: Sayre L. M. et. al., J. Med. Chem., 27, 1325, 1984.
Non-Patent Literature 5: Simon C. et. al., Synth. Commun., 22, 913, 1992.